DESCRIPTION: (adapted from the application): The goal of this project is to test the role of decreased plasma glucose in the anti-aging action of dietary restriction (DR). The effect of DR in chronically lowering plasma glucose levels has been demonstrated in mice, rats and non-human primates using a variety of different regimens. The consistency of this finding suggests that decreased plasma glucose may be an important consequence of DR and that it may be mechanistically involved in the retardation of aging. Such a role is suggested by current knowledge of both DR and aging: DR exerts protective effects on cellular homeostasis by enabling appropriate rates of glucose utilization to occur at lower circulating levels of this reactive fuel; the Glycation Theory of Aging and related theories suggest that glucose-mediated glycation of macromolecules and/or the generation of glycoxidation products are mechanistically involved in aging and in age-related diseases such as diabetes and atherosclerosis. Project 2 will test the following hypothesis: Decreased plasma glucose over the lifespan is an important component of the action of dietary restriction on aging. If decreased plasma glucose play a role in the anti- aging action of DR, then lowering of plasma glucose without reduction of food intake should also retard the aging process. This hypothesis will be tested using a transgenic mouse that over expresses the GLUT4 glucose transporter protein. These mice have reduced levels of plasma glucose over their lifespan but consume the same amount of food as non-transgenic mice. In addition, DR further lowers plasma glucose in the GLUT4 transgenic mice. Thus, mice having grade levels of plasma glucose over their lifespan can be produced using transgenic and non-transgenic mice fed ad libitum or a restricted diet (40% less than ad libitum). These four groups of mice will be used to test the hypothesis by executing the following specific aims: (1) To determine if longevity is increased and if age-related incidence of disease and age-related functional decline are decreased in mice having lower levels of plasma glucose. (2) To determine if whole body metabolism and parameters of glucose homeostasis are different in transgenic versus non-transgenic mice. (3) To determine if tissue glycation, glycoxidation and oxidation are altered in transgenic mice versus non-transgenic mice.